Search Results (1,568)

Neohesperidin dihydrochalcone (NHDC) has been confirmed to possess excellent nutritional activities as a natural flavonoid low-calorie sweetener, but its practical application in the food industry was greatly limited due to its low water solubility. The potential NHDC activity against oxidative stress (OS) diseases was explored through network pharmacology and molecular docking technology, and a highly water-soluble NHDC-L-arginine complex (NL) was prepared by combining NHDC with L-arginine to overcome this technical bottleneck. Meanwhile, the enhancement of antioxidant capacity markers under non-stressed conditions following NL treatment was systematically investigated in Caenorhabditis elegans (C. elegans), and transcriptomic and metabolomic analyses were integrated to reveal the potential regulatory mechanism at the molecular and metabolic levels. It was found that NHDC could exert potential anti-OS effects by targeting and binding to key proteins such as CYP19A1, TYR, EPHX2, TDP1, ESR1, and SLC5A1. In addition, the MDA level in C. elegans after NL intervention was significantly reduced to 0.65 ± 0.06 nmol/mg prot, while the activities of antioxidant enzymes T-SOD, GSH-Px, and CAT were significantly increased to 48.83 ± 1.75 U/mg prot, 112.95 ± 0.55 U/mg prot, and 6.30 ± 0.16 U/mg prot, respectively. Longevity regulating pathway–worm was identified as a potential key signaling pathway for NL to regulate the enhancement of antioxidant capacity markers under non-stressed conditions of C. elegans at the molecular level, and the pentose phosphate pathway was the core metabolic pathway. These results could offer theoretical support for the potential development of NHDC and NL in the field of antioxidants, as well as their large-scale applications in the functional food and flavored food industries. Full article

Despite the growing knowledge about ovarian cancer, it has not yet been possible to develop an effective screening test for this cancer. Therefore, it seems necessary to identify new risk factors, such as genetic polymorphisms. The aim of this study was to demonstrate whether polymorphisms of the ESR1 gene rs2234693 and rs9340799 may be involved in the development of ovarian cancer. The material for the study was DNA obtained from 100 ovarian cancer patients and 100 control groups. Polymorphisms were determined using the PCR-RFLP technique. The presence of the CC genotype (rs2234693) has been shown to more than double the risk of ovarian cancer (OR 2.21; p = 0.041). In the case of the second polymorphism, rs9340799, the carrier of the GG genotype more than doubles the risk of ovarian cancer (OR 2.62 p = 0.031). Analysis of ESR1 gene haplotypes in relation to the rs2234693 and rs9340799 polymorphisms showed that the occurrence of TCAG and CCGG systems may be associated with a significant increase in the risk of ovarian cancer (OR 1.98, p = 0.043 and OR 2.45, p = 0.041, respectively). In the group of patients with ovarian cancer, a correlation was shown between the polymorphisms rs2234693 and rs9340799 in the tissues of ovarian cancers with the lowest stage compared to more advanced ovarian cancers, which may indicate a relationship between these factors and the stage of the tumor. Women’s age had no effect on the prevalence of individual genotypes or the associated risk of disease. Polymorphisms rs2234693 and rs9340799 of the ESR1 gene may be associated with the occurrence of ovarian cancer. Full article

Background: Despite mesalamine’s efficacy in mild-to-moderate ulcerative colitis (UC), many patients fail to achieve complete clinical or biochemical remission. Pentoxifylline (PTX) may act as an adjunct therapy by modulating cytokine production and oxidative stress. Aim: To evaluate the therapeutic effect of adding PTX in patients with UC. Methods: In this randomized, double-blind, placebo-controlled pilot study, 60 patients with UC were assigned to mesalamine plus placebo (Group 1) or mesalamine plus PTX 400 mg BID (Group 2) for 24 weeks. The primary outcome was changes in the partial Mayo score (PMS). Clinical remission was defined as PMS ≤ 2 with no subscore > 1; clinical response as a reduction in PMS ≥ 2 points. Quality of life (QoL) was measured using the Inflammatory Bowel Disease Questionnaire (IBDQ-32). Serum TNF-α, fecal calprotectin, and erythrocyte sedimentation rate (ESR) were assessed. Analyses were performed using intention-to-treat (ITT) and per-protocol (PP) approaches. Subgroup analyses stratified by prior mesalamine exposure, and multivariable regression adjusted for age, sex, disease duration, smoking, and disease extent. Results: PTX significantly improved PMS compared to placebo in both ITT and PP analyses. Clinical response and remission rates were higher with PTX. IBDQ-32 scores increased, and TNF-α, calprotectin, and ESR decreased significantly more with PTX. Improvements were consistent across mesalamine-naïve and experienced patients. Multivariable regression confirmed that these effects were independent of demographic or disease-related confounders. Conclusions: Adjunctive PTX significantly enhanced clinical outcomes, reduced inflammation, and improved QoL in UC patients, supporting its potential as an effective add-on therapy to mesalamine. Full article

Objective: The aim of this case series was to investigate the safety and efficacy of vancomycin–gentamicin embedded PMMA beads (VGPB) in the setting of acute pyogenic soft tissue infections (STIs) of the extremities. Materials and Methods: A retrospective study of 19 cases diagnosed with pyogenic STIs of the lower or upper extremity in two academic institutions was conducted between January 2017 and December 2023. All patients underwent surgical debridement, systemic antibiotics and intrawound deposition of vancomycin and gentamicin embedded cement beads (2 g of vancomycin plus 1 g of gentamicin diluted in 40 g of PMMA). Upon second look (4th–7th day post-index surgery) the cement beads were removed, serum samples from the surgical site of infection and from peripheral blood were obtained and the concentration of eluted vancomycin and gentamicin was measured. Furthermore, the white blood cell count (WBC), C reactive protein serum levels (CRP) and erythrocyte sedimentation rate (ESR) were measured before the surgical debridement and after the end of the bead therapy. All patients were reevaluated after discharge with a mean follow-up of 4.4 years (range, 1 to 7.6). Results: Wound vancomycin and gentamicin levels were significantly higher than those measured in the serum (34.01 ± 4.47 μg/mL versus 11.96 ± 2.79 μg/mL, p < 0.001 and 5.75 ± 1.22 μg/mL versus 0.51 ± 0.14 μg/mL, p < 0.001 respectively). Serum vancomycin and gentamicin concentrations were below the level of toxicity and no adverse events related to antibiotic-embedded bead treatment were documented. Serum WBC, ESR and CRP levels before debridement (13,446 ± 935.7 c/μL, 42.3 ± 18.7 mm/h and 113.9 ± 20.26 mg/L respectively) were significantly higher than those after the end of treatment (7889 ± 1203.6 c/μL, p < 0.001; 30.3 ± 9.14 mm/h, p = 0.017; and 22.7 ± 6.68 mg/L, p < 0.001 respectively). Two cases (10.5%) had a local recurrence of their STIs. Both of them relapsed within 4 months after their treatment and both had Gram-negative pathogens. Conclusions: Vancomycin–gentamicin PMMA bead pouch therapy appears to be a safe and effective adjuvant treatment for pyogenic soft tissue infections, offering high local antibiotic availability without systemic adverse effects. Full article

Heavy radioactive ion beams produced by in-flight techniques often involve long-lived excited states (isomers). This presents a challenge for reaction studies because none of the existing fragment separators worldwide can resolve isomers in-flight. Here, we propose a novel scheme to produce tagged cocktail beams or pure isomer beams using an ion storage ring. The mass resolving powers of storage rings enable us to identify and separate ions of the isomeric state from the corresponding ground state in a secondary beam. For short-lived isomers, the Rare-RI Ring (R3) facility at the RI Beam Factory (RIBF) will be available, while for long-lived isomers the Experimental Storage Ring (ESR) at the GSI/FAIR facility will be utilized. Isomers often have spins and deformations significantly different from the ground states. Studying isomer structures will provide unique insight into their specific interactions, opening a new frontier in reaction studies with radioactive ion beams in the coming years. Full article

The perception that hormonal contraception causes weight gain is a general belief that frequently hinders the initiation and continuation of effective family planning. This narrative review analyses data from Cochrane systematic reviews and recent pharmacogenomic studies to separate patient perception from metabolic reality. Analysis of high-quality data, including Cochrane systematic reviews, indicates that the association between Combined Hormonal Contraceptives (CHCs)—including oral pills, the transdermal patch, and the vaginal ring—and weight gain is not supported by consistent high-quality evidence. Placebo-controlled trials demonstrate that these methods are weight-neutral on average. Perceived weight increases in CHC users are likely mediated in part by fluid retention linked to the estrogenic stimulation of the Renin–Angiotensin–Aldosterone System (RAAS), rather than adipose tissue accumulation. Conversely, Depot Medroxyprogesterone Acetate (DMPA) represents a verified clinical risk for weight gain, showing a demonstrated clinical association with significant fat mass accumulation. Hypothesized biological mechanisms for this increase include hypothalamic appetite stimulation and glucocorticoid-like activity. The etonogestrel implant occupies a complex middle ground. While population-level data suggests weight neutrality, recent exploratory pharmacogenomic research has identified a specific variant in the Estrogen Receptor 1 (ESR1) gene. For the minority of women carrying this variant, the implant may trigger clinically significant weight gain, suggesting a biological basis for their subjective experience despite statistical evidence. Ultimately, the persistence of the weight gain concern is fueled by the nocebo effect and the misattribution of natural age-related weight trajectories to contraceptive use. Full article

This paper presents a fuzzy satisfaction-based intelligent framework for early-stage multiobjective sizing of a buck DC–DC converter under uncertain operating conditions. Lightweight closed-form estimators are used to evaluate inductor current ripple, output voltage ripple, and efficiency, including an explicit decomposition of ripple into capacitive and ESR-induced components to distinguish capacitance-dominated and ESR-dominated regimes. Engineering targets for ripple, efficiency, and passive size/cost pressure are mapped to reproducible piecewise membership functions and aggregated into a bounded overall satisfaction score using a weighted geometric operator; alternative non-compensatory and OWA-type aggregators are considered for sensitivity analysis. The resulting nonconvex design problem is solved via a compact two-stage derivative-free strategy that combines global screening with an interpretable Takagi–Sugeno (TSK) rule-based refinement layer, which generates bounded, physics-consistent updates of the design variables and supports rapid feasibility restoration followed by preference-driven tuning. Uncertainty in operating conditions and parameter drift is addressed through scenario evaluation and worst-case or average-case aggregation of satisfaction, linking the fuzzy decision objective to robust scenario design. Numerical studies for a 24 ± 4 V to 12 V converter illustrate regime-dependent adaptation: in low-ESR conditions, ripple improvement is driven mainly by capacitance/frequency adjustments, while in high-ESR conditions, the rule base shifts corrections toward inductor and frequency choices that reduce ESR-dominated ripple. Full article

Background: Type 2 diabetes mellitus (T2DM) is characterized by chronic low-grade inflammation that contributes to cardiometabolic complications. While diabetes duration reflects cumulative metabolic exposure, its relationship with systemic inflammatory burden remains insufficiently defined. We aimed to investigate inflammatory patterns across diabetes duration and to explore their metabolic and cardio–renal correlates. Methods: This real-world cross-sectional study included 250 adults with T2DM. Diabetes duration was analyzed both continuously and across four predefined strata (0–4, 5–9, 10–14, and ≥15 years). Inflammatory burden was assessed using C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Given the skewed distribution of CRP, log-transformed CRP was used in regression analyses. Nonlinear associations were evaluated using quadratic regression models. This approach was selected because preliminary descriptive analyses suggested a non-monotonic relationship between diabetes duration and CRP levels. Inclusion of a quadratic term allowed formal testing of a potential curvilinear association between diabetes duration and inflammatory burden. Spearman correlations were performed to assess associations with metabolic, renal, and cardiovascular variables. Results: CRP showed a nonlinear cross-sectional association across diabetes duration strata. Median CRP values were higher in early (0–4 years: 0.62 mg/L) and long-standing diabetes (≥15 years: 0.77 mg/L) compared with intermediate-duration groups (p = 0.063). Quadratic regression confirmed a U-shaped relationship (adjusted β_duration = −0.079, p < 0.001; β_duration² = 0.0027, p < 0.001; R² = 0.326). ESR differed significantly across duration strata (p = 0.002), with the highest levels observed in long-standing diabetes. CRP correlated positively with BMI (ρ = 0.151; p = 0.017) and triglyceride-to-HDL ratio (ρ = 0.215; p < 0.001), but not with HbA1c. Both CRP and ESR were more strongly associated with functional CKD (ρ = 0.350 and 0.429, respectively; p < 0.001) than with ASCVD. Conclusions: Inflammatory burden in T2DM shows a nonlinear cross-sectional pattern across diabetes duration, characterized by elevated levels in early and long-standing disease. Systemic inflammation appears more closely linked to renal dysfunction than to established cardiovascular disease. These findings support a cardio–renal–inflammatory axis in which prolonged diabetes exposure contributes to renal decline, which in turn amplifies systemic inflammatory activation. Full article

The freshwater snail Bellamya purificata is both ecologically and economically significant, exhibiting notable sexual dimorphism in growth and nutritional traits that underscore the importance of breeding of monosex stocks. However, the genetic basis of sex determination remains unclear. Herein, genome-wide association studies (GWASs) combined with transcriptomic analysis were conducted to identify sex-linked markers and candidate genes for this species. GWAS generated 571 significantly sex-associated SNPs and 1853 InDels, corresponding to 44 candidate genes. Multiple significant SNP peaks were detected on chromosomes 1 and 2, with mrc2 and mis18bp1 as key candidate genes. A sex-linked InDel marker located within mis18bp1 can distinguish males and females cost-effectively. Genotype analysis of the sex-associated loci revealed that most females were homozygous while males were heterozygous, suggesting that B. purificata has a primarily XX/XY sex determination system. Comparative gonadal transcriptome analyses identified 2996 female-biased and 4281 male-biased genes. Among them, sry, sox8, dmrt1 and dmrt2 may be critical in male sex differentiation, while β-catenin, foxl2, esr1 and nr5a2 may be important in female sex differentiation. Integration of GWAS and transcriptomic data highlighted four pronounced sex-associated candidate genes, including mis18bp1, rnf216, tbx1 and mrc2. These results provide a valuable foundation for elucidating the genetic mechanisms underlying sex determination and for the development of monosex stocks in B. purificata. Full article

Background: Up to one-third of brucellosis patients develop focal organ involvement, contributing to increased morbidity and therapeutic failure, yet no clinically validated instrument exists to stratify risk at presentation. Methods: In this three-center retrospective cohort from Türkiye (2015–2025), 355 adults with confirmed brucellosis were enrolled. Thirty-two candidate variables spanning demographics, comorbidities, symptoms, routine laboratory values, and composite inflammation indices underwent LASSO-penalized regression with 10-fold cross-validation for predictor selection, after which a nomogram was constructed and internally validated via 1000-iteration bootstrap resampling. Results: Ninety-two patients (25.9%) developed focal complications. Five predictors were retained by LASSO—prognostic nutritional index (PNI), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), chronic disease stage, and hypertension—and combined with age and sex (retained a priori) into a seven-predictor nomogram. PNI was the strongest contributor (OR = 0.901, 95% CI: 0.857–0.948). Apparent C-statistic reached 0.782 (optimism-corrected 0.762), with a calibration slope of 0.894 and Brier score of 0.154. Decision curve analysis indicated net clinical benefit over the 5–55% threshold probability range. Conclusions: This PNI-anchored LASSO nomogram offers a practical bedside risk stratification instrument for brucellosis-related focal involvement. Prospective external validation across geographically diverse endemic regions is warranted before clinical adoption. Full article

We propose Adaptive Inference, a portfolio management framework extending Active Inference to non-stationary financial environments. The framework integrates inference, control, and execution under endogenous uncertainty, modeling investment decisions as coupled dynamics of belief updating, preference encoding, and action selection rather than optimization over fixed objectives. In this approach, portfolio behavior is governed by the expected free energy (EFE) minimization, showing that classical valuation models emerge as limiting cases when epistemic components vanish. Using train–test evaluation on the ARKK Innovation ETF (2015–2025), we identify a Passivity Paradox: frozen belief transfer outperforms naive adaptive learning. A Professional Agent achieves a Sharpe ratio of 0.39 while its adaptive counterpart degrades to $-0.28$, reflecting belief contamination when learning from policy-dependent signals. Crucially, the architecture is not designed to generate alpha but to perform endogenous risk management that mitigates overtrading under regime ambiguity and distributional shift. Adaptive Inference Agents maintain long exposure most of the time while tactically reducing positions during high-entropy periods, implementing uncertainty-aware passive investing. All agents reduce realized volatility relative to ARKK Buy-and-Hold (43.0% annualized). Cross-asset validation on the S&P 500 ETF (SPY) shows that inference-guided risk shaping achieves a positive Entropic Sharpe Ratio (ESR), defined as excess return per unit of informational work, thereby quantifying the economic value of information under thermodynamic constraints on inference. Full article

Polyester microfibers (MF) are widespread in aquatic environments and increasingly recognized as an emerging factor affecting fish physiology. This study aimed to investigate the effects of intestinal accumulation of MF on gut tissue and cellular alterations, as well as on the HPG axis and oocyte maturation in adult female zebrafish. Adult female zebrafish were exposed to environmentally relevant concentrations of MF (1000 and 3000 particles/L) for 14 days to examine endocrine-regulated physiological and reproductive responses. For comparative reference, a bisphenol A (BPA) exposure group was included to contextualize endocrine-related responses. MF exposure resulted in intestinal accumulation. Gene expression analyses showed increased expression of vtg1 and esr2a, along with decreased expression of gnrh3, fshβ, lhβ, cyp17, and cyp19a1, indicating altered regulation of the HPG axis and steroidogenic pathways. Ovarian histology revealed alterations in oocyte development, especially at the higher MF concentration, indicating that MF can affect endocrine-regulated physiology and reproduction in fish. Together, these findings provide new evidence that intestinal accumulation of microfibers, along with associated histological and transcriptional alterations, elicits estrogen-responsive physiological patterns that influence HPG axis regulation and oocyte maturation in fish. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is a primary malignancy often driven by metabolic syndrome, fatty liver disease, and chronic hepatitis. These conditions foster a pro-inflammatory microenvironment that promotes tumor progression. Viniferin, a natural oligostilbene, has gained attention for its potential bioactivity. This study utilized an in silico network pharmacology approach to elucidate the pharmacokinetic properties and molecular mechanisms of ε- and δ-viniferin against HCC within the context of metabolic and inflammatory liver pathologies. Methods: ADMET profiles were characterized using SwissADME and pkCSM. Therapeutic targets were identified by intersecting viniferin-associated molecules with disease genes from GeneCards. A protein–protein interaction (PPI) network was constructed, supplemented by GO and KEGG enrichment analyses. Molecular docking and 200 ns of molecular dynamics (MD) simulations evaluated the binding affinity and structural stability between viniferin isomers and identified hub proteins. Results: Both ε- and δ-viniferin showed favorable drug-like properties, including high gastrointestinal absorption and low hepatotoxicity. We identified 247 overlapping targets, with network analysis highlighting ten essential hub genes, including AKT1, HSP90AA1, ESR1, HIF1A, NFKB1, GSK3B, PTGS2, APP, MTOR, and PIK3CA. Enrichment analysis confirmed their involvement in critical oncogenic pathways. Molecular docking showed strong interactions with APP, HSP90AA1, and AKT1, while MD simulations validated the long-term stability of ε-viniferin within the APP binding pocket. Conclusions: These findings provide mechanistic insights into viniferin as a multi-target agent for HCC, justifying further experimental validation in pre-clinical models. Full article

Background: Continuity of care for rheumatoid arthritis patients within regional networks enables stable long-term clinical data collection, despite chronic rheumatologist shortages in Japan. We determined 5-year drug survival and discontinuation reasons for eight biological disease-modifying antirheumatic drugs (bDMARDs) using a regional multicenter registry. Methods: We retrospectively analyzed 1182 patients initiating their first (naïve, n = 784) or subsequent (switch, n = 398) bDMARD between May 2001 and August 2022 across five institutions. The primary endpoint (5-year drug survival) and secondary endpoints (discontinuation risk factors and cumulative incidence of reasons) were evaluated using Kaplan–Meier curves, Cox proportional hazards, and Fine & Gray models. Results: Baseline characteristics varied significantly among bDMARDs. Five-year drug survival in the naïve cohort ranged from tocilizumab (50.8%) to golimumab (22.6%); in the switch cohort, from abatacept (42.6%) to infliximab (10.0%). In multivariable Cox analysis of naïve patients, male sex (hazard ratio [HR] = 1.49, 95% confidence interval [CI] = 1.09–2.02), lower baseline 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) (HR = 0.90, 95% CI = 0.82–0.99), and absence of methotrexate co-therapy (HR = 0.73, 95% CI = 0.55–0.97) predicted discontinuation. The lower baseline DAS28-ESR association potentially reflects successful courses toward intentional cessation following remission. Discontinuations were attributed to inadequate response (27.1%), non-adverse events (25.3%), and adverse events (17.3%). Conclusions: Tocilizumab and abatacept demonstrated the highest retention rates in biologic-naïve and switch cohorts, respectively. Early, individualized drug selection and dose optimization are crucial to maximizing long-term bDMARD effectiveness before switching. Full article

Having appropriate and meaningful diagnostic procedures is crucial in the approach to patients with chronic spontaneous urticaria (CSU), so we wanted to investigate relationships between CSU patients’ common serum factors and clinical CSU features, and their temporal trends during antihistamine treatment. In this exploratory hypothesis-based study, we assessed disease severity and quality of life (QoL) in, initially, 41 CSU patients using UAS7, daily UAS, UCT, DLQI, and CU-Q2oL. Concurrently, we measured serum complete blood count (CBC), total IgE, thyroid antibodies and hormones, ANA, D-dimer, vitamin D, and the inflammatory molecules CRP, ESR and IL-6. We compared initial (T1) and follow-up findings (T2) (after 3 months of antihistamine therapy). Basophil concentration was the only examined serum factor useful in assessing current CSU severity/daily UAS (sensitivity 78.6%; specificity 63%; p = 0.028). Basopenia was more frequent in patients with moderate/severe CSU than in those with mild disease or remission, as measured by daily UAS (79% vs. 37%; p = 0.020). T4 values showed a significant dependence on CSU duration (r = −0.328; p = 0.036). ESR was the only examined serum factor significantly associated with weekly CSU severity (UAS7) (p = 0.038). Antihistamine treatment significantly reduced CSU activity (recorded by daily UAS and UAS7) and improved QoL (DLQI) (p = 0.006) and disease control/UCT (p = 0.005). After three months of treatment, only the CRP value correlated with CSU control/UCT (p = 0.014). We encourage the use of diagnostics employing basophil counts and clinical indices UAS7, daily UAS, UCT and DLQI for insight into a patient’s CSU clinical condition. Serum factor values did not change during the 3-month treatment period, so it is not useful to measure them repeatedly. Although this study involved a small cohort and has many limitations, these promising results highlight the need for replication with a greater number of CSU patients. Full article